Differences between the sexes among genetic variants affecting orofacial cleft birth defect risk

影响口颌裂出生缺陷风险的基因变异的性别差异

基本信息

批准号：
10602447
负责人：
Mary L. Marazita
金额：
$ 40.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602447
关键词：
Accounting Affect African Anatomy Asian population Birth CDH1 gene Categories Cleft Lip Cleft Palate Cleft lip with or without cleft palate Collection Complex Congenital Abnormality Craniofacial Abnormalities Data Databases Detection Epidemiology Ethnic Population Etiology European Family Family Study Female Genes Genetic Genetic Heterogeneity Genetic Predisposition to Disease Genetic study Genome Scan Genomics Genotype Heritability Heterogeneity Human Infant Link Live Birth Methods Nonsense Mutation Nucleotides Parents Pattern Penetrance Population Prevalence Procedures Recording of previous events Reporting Research Risk Sex Differences Subgroup Syndrome Testing Twin Studies Validation Variant X Chromosome autosome causal variant cleft lip and palate de novo mutation design follow-up genetic architecture genetic pedigree genetic variant genome wide association study genome-wide analysis genomic data in silico male malformation multi-ethnic novel orofacial cleft population based proband rapid testing rare variant risk sharing sex trait transmission process

项目摘要

PROJECT SUMMARY Orofacial clefts (OFCs) represent the most common group of craniofacial malformations in humans affecting approximately one per 1,000 live births worldwide. OFCs include cleft lip (CL), cleft palate (CP) and cleft lip with cleft palate (CLP), which can occur as isolated malformations, with another malformation or as part of a recognized malformation syndrome (often Mendelian with incomplete penetrance). OFCs are commonly categorized into two anatomically and embryologically distinct entities based on embryologic and epidemiologic patterns: cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Among all infants born with an OFC, 70 percent of CL/P cases and 50 percent of CP cases occur as isolated, non-syndromic malformations. Non-syndromic CL/P occurs more frequently in males than females (ratio 2:1) whereas non-syndromic CP occurs more often in females (ratio approximately 1:1.14). Substantial variation in birth prevalence rates of non- syndromic CL/P has been reported across populations, with Asian populations having higher birth prevalence rates compared to European populations, and African populations having the lowest birth prevalence rates. Risk to OFC shows strong evidence of genetic control with estimated heritability up to 90%. Recent genome- wide association studies have clearly shown multiple genes play a role in the etiology of OFCs, but with substantial heterogeneity among families and across populations. To date, approximately 50 different genes have been identified as significant in such genome-wide studies of OFCs, with about two dozen having substantial replication and/or functional studies. However, despite a long history of scientific research into the genetic control of OFC, much of the heritability remains unexplained (which may reflect the genetic heterogeneity influencing risk to OFC, where a number of different genes with both rare and common variants control risk), and it remains difficult to clearly identify underlying causal genes. Moreover, sex differences in risk to OFC and parent-of-origin effects traditionally have not been the focus of genetic studies, and X chromosome variants have largely been ignored. In this application, we are using existing genomic data from family-based studies in different ethnic groups to specifically study the underlying mechanisms for differential risk to OFC between the sexes. Specifically, we will (i) use case-parent trios to detect different genetic OFC risk effect sizes and parent of origin effects, (ii) use a novel method to characterize sex differences in the genetic architecture of OFCs accounting for potential cleft type differences and similarities, and (iii) conduct association tests for variants on the X chromosome. In addition, we will use genomic data from extended multiplex pedigrees to identify highly penetrant genomic X-linked variants. The family-based designs allow us to study common and rare variants, parent-of origin effects, and allow us to assess the impact of de novo variants. In all aims, we will attempt to use functional data from external data bases to conduct an “in silico” validation of our findings.

项目概要口面裂（OFC）是人类最常见的颅面畸形，影响全球大约每 1,000 名活产儿中就有 1 名 OFC 包括唇裂 (CL)、腭裂 (CP) 和唇裂。腭裂 (CLP)，可作为孤立的畸形、与其他畸形一起发生或作为畸形的一部分发生公认的畸形综合征（通常是具有不完全外显率的孟德尔畸形综合征）。根据胚胎学和流行病学分为两个解剖学和胚胎学不同的实体模式：唇裂伴或不伴腭裂（CL/P）和单纯腭裂（CP）。 OFC、70% 的 CL/P 病例和 50% 的 CP 病例都是孤立的、非综合征性畸形。非综合征性 CL/P 在男性中的发生率高于女性（比例为 2:1），而非综合征性 CP 则发生率较高女性更常见（比例约为 1:1.14）。 CL/P 综合征在人群中均有报道，其中亚洲人群的出生率较高与欧洲人口和出生率最低的非洲人口相比。 OFC 风险显示出遗传控制的有力证据，估计遗传力高达 90%。广泛关联研究清楚地表明多个基因在 OFC 的病因学中发挥作用，但迄今为止，大约有 50 个不同的基因在家庭和人群之间存在显着的异质性。已被认为在 OFC 的此类全基因组研究中具有重要意义，其中大约有两打具有然而，尽管科学研究有着悠久的历史。由于 OFC 的遗传控制，许多遗传力仍然无法解释（这可能反映了遗传异质性）影响 OFC 的风险，其中许多具有罕见和常见变异的不同基因控制风险），以及此外，要明确确定 OFC 风险的性别差异仍然很困难。传统上，亲本效应并不是遗传学研究的焦点，而 X 染色体变异已经成为遗传研究的焦点。在这个应用程序中，我们使用来自不同家庭的研究的现有基因组数据，这在很大程度上被忽略了。种族群体专门研究性别之间 OFC 风险差异的潜在机制。具体来说，我们将 (i) 使用案例-父母三重奏来检测不同的遗传性 OFC 风险效应大小和父母来源效应，(ii) 使用一种新方法来表征 OFC 核算遗传结构中的性别差异潜在的裂隙类型差异和相似性，以及 (iii) 对 X 上的变异进行关联测试此外，我们将使用来自扩展多重谱系的基因组数据来高度识别。基于家族的设计使我们能够研究常见和罕见的变异，亲本效应，并允许我们评估从头变异的影响。在所有目标中，我们将尝试使用。来自外部数据库的功能数据对我们的发现进行“计算机”验证。